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EP2970296B1 - Pyrrolotriazine als kaliumionenkanalhemmer - Google Patents

Pyrrolotriazine als kaliumionenkanalhemmer Download PDF

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Publication number
EP2970296B1
EP2970296B1 EP14713005.8A EP14713005A EP2970296B1 EP 2970296 B1 EP2970296 B1 EP 2970296B1 EP 14713005 A EP14713005 A EP 14713005A EP 2970296 B1 EP2970296 B1 EP 2970296B1
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EP
European Patent Office
Prior art keywords
triazin
phenyl
pyridin
pyrrolo
phenylpyrrolo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
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EP14713005.8A
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English (en)
French (fr)
Other versions
EP2970296A1 (de
Inventor
Heather Finlay
Ashok Kumar Adisechan
Naveen Kumar Dhondi
Govindrajulu KAVITHA
Prashantha Gunaga
John Lloyd
Pothukanuri Srinivasu
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Publication of EP2970296A1 publication Critical patent/EP2970296A1/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention provides for pyrrolotriazines useful as inhibitors of potassium channel function (especially inhibitors of the K v 1 subfamily of voltage gated K + channels, more especially inhibitors of K v 1.5 (which have been linked to the ultra-rapidly activating delayed rectifier K + current I Kur ), and/or K v 1.3 channels, and/or K v 1.1 channels) and to pharmaceutical compositions containing such compounds.
  • the present invention further provides such compounds for use in the treatment and prevention of arrhythmia, I Kur -associated disorders, and other disorders mediated by ion channel function.
  • the ultra-rapidly activating delayed rectifier K + current (I Kur ) is believed to represent the native counterpart to a cloned potassium channel designated K v 1.5 and, while present in human atrium, it appears to be absent in human ventricle. Furthermore, because of its rapidity of activation and limited slow inactivation, I Kur is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of I Kur , that is a compound which blocks K v 1.5, would overcome the short coming of other compounds by prolonging refractoriness by retarding repolarization in the human atrium without causing the delays in ventricular repolarization that underlie arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class III antiarrhythmic agents. (Antiarrhythmic agents of Class III are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression.)
  • Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves' ophthalmopathy and asthma. Although the underlying pathogenesis of each of these conditions may vary, they have in common the appearance of a variety of auto-antibodies and self-reactive lymphocytes.
  • Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates.
  • lymphocytes recognize the foreign tissue antigens and begin to produce immune mediators which lead to graft rejection or graft-vs-host rejection.
  • autoimmune or a rejection process tissue destruction caused by inflammatory cells and the mediators they release.
  • Anti-inflammatory agents such as NSAIDs act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease.
  • cytotoxic agents such as cyclophosphamide, act in such a nonspecific fashion in which both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb to infection as they are to their autoimmune disease.
  • Cyclosporin A which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs.
  • FK-506 PROGRAF®
  • Cyclosporin A was approved by the US FDA for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis. Though these agents are effective in fighting transplant rejection, Cyclosporin A and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort.
  • Inhibitors of K v 1.5 and other K v 1.x channels stimulate gastrointestinal motility.
  • the compounds of the invention are believed to be useful in treating motility disorders such as reflux esophagitis. See Frey et al., "Blocking of cloned and native delayed rectifier K channels from visceral smooth muscles by phencyclidine", Neurogastroenterol. Motil., 12(6):509-516 (Dec. 2000 ); Hatton et al., "Functional and molecular expression of a voltage-dependent K(+) channel (Kv1.1) in interstitial cells of Cajal", J. Physiol., 533(Pt 2):315-327 (Jun.
  • Vianna-Jorge et al. "Shaker-type Kv1 channel blockers increase the peristaltic activity of guinea-pig ileum by stimulating acetylcholine and tachykinins release by the enteric nervous system", Br. J. Pharmacol., 138(1):57-62 (Jan. 2003 ); Koh et al., "Contribution of delayed rectifier potassium currents to the electrical activity of murine colonic smooth muscle", J. Physiol., 515(Pt. 2):475-487 (Mar. 1, 1999 ).
  • Inhibitors of K v 1.5 relax pulmonary artery smooth muscle.
  • the compounds of the invention are believed to be useful in treating hypertension and otherwise improving vascular health. See Davies et al., "Kv channel subunit expression in rat pulmonary arteries", Lung, 179(3):147-161 (2001 ), Epub. Feb. 4, 2002; Pozeg et al., "In vivo gene transfer of the 02-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats", Circulation, 107(15):2037-2044 (Apr. 22, 2003 ), Epub. Apr. 14, 2003.
  • Inhibitors of K v 1.3 increase insulin sensitivity.
  • the compounds of the invention are believed to be useful in treating diabetes. See Xu et al., "The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity", Proc. Natl. Acad. Sci. U.S.A., 101(9):3112-3117 (Mar. 2, 2004 ), Epub. Feb. 23, 2004; MacDonald et al., "Members of the Kv1 and Kv2 voltage-dependent K(+) channel families regulate insulin secretion", Mol. Endocrinol., 15(8):1423-1435 (Aug.
  • Stimulation of K v 1.1 is believed to reduce seizure activity by hyperpolarizing neurons.
  • the compounds of the invention are believed to be useful in treating seizures, including seizures associated with epilepsy and other neurological diseases. See Rho et al., "Developmental seizure susceptibility of kv1.1 potassium channel knockout mice", Dev. Neurosci., 21(3-5):320-327 (Nov. 1999 ); Coleman et al., "Subunit composition of Kv1 channels in human CNS", J. Neurochem., 73(2):849-858 (Aug.
  • K v 1.x channels improves cognition in animal models.
  • the compounds of the invention are believed to be useful in improving cognition and/or treating cognitive disorders. See Cochran et al., "Regionally selective alterations in local cerebral glucose utilization evoked by charybdotoxin, a blocker of central voltage-activated K+-channels", Eur. J. Neurosci., 14(9):1455-1463 (Nov. 2001 ); Kourrich et al., "Kaliotoxin, a Kv1.1 and Kv1.3 channel blocker, improves associative learning in rats", Behav. Brain Res., 120(1):35-46 (Apr. 8, 2001 ).
  • WO 2009/026254 discloses heterocycles, compositions and methods useful in the treatment of central or peripheral nervous system disorders and as neuroprotective agents by modulating potassium channels associated with the onset or recurrence of such conditions.
  • WO 00/71129 discloses compounds which inhibit the tyrosine kinase activity of growth factor receptors, thereby making them useful as anti-cancer agents.
  • arrhythmias such as atrial fibrillation, atrial flutter, supraventricular arrhythmias
  • gastrointestinal disorders such as reflux esophagitis or a motility disorder
  • inflammatory or immunological disease such as chronic obstructive pulmonary disease
  • diabetes cognitive disorders
  • migraine epilepsy
  • hypertension or treating I Kur -associated conditions, or controlling heart rate.
  • compositions comprising a therapeutically effective amount of at least one compound described herein and a pharmaceutically acceptable vehicle or carrier thereof.
  • Such compositions can further comprise one or more other agent(s).
  • at least one other anti-arrhythmic agent such as sotalol, dofetilide, diltiazem or Verapamil
  • at least one calcium channel blocker or at least one anti-platelet agent (such as clopidogrel, cangrelor, ticlopidine, CS-747, ifetroban and aspirin)
  • at least one anti-hypertensive agent such as a beta adrenergic blocker, ACE inhibitor ( e .
  • captopril zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, or lisinopril
  • a II antagonist ET antagonist, Dual ET/A II antagonist, or vasopepsidase inhibitor ( e .
  • thrombotic/anti thrombolytic agent such as tPA, recombinant tPA, TNK, nPA, factor VIIa inhibitors, factor Xa inhibitors (such as apixaban), factor XIa inhibitors or thrombin inhibitors), or at least one anti coagulant (such as warfarin or a heparin), or at least one HMG-CoA reductase inhibitor (pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 or ZD-4522), or at least one anti diabetic agent (such as a biguanide or a biguanide/glyburide combination), or at least one thyroid mimetic, or at least one mineralocorticoid receptor antagonist (such as spironolactone or eplerinone), or at least one cardiac glycoside (such as digitalis or ouabain
  • Another aspect of this invention is directed to a compound of the present invention or an individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by inhibitors of potassium channel function (especially inhibitors of the K v 1 subfamily of voltage gated K + channels, more especially inhibitors of K v1 .5 (which have been linked to the ultra-rapidly activating delayed rectifier K + current I Kur ), and/or K v 1.3 channels, and/or K v 1.1 channels).
  • inhibitors of potassium channel function especially inhibitors of the K v 1 subfamily of voltage gated K + channels, more especially inhibitors of K v1 .5 (which have been linked to the ultra-rapidly activating delayed rectifier K + current I Kur ), and/or K v 1.3 channels, and/or K v 1.1 channels).
  • Another aspect of this invention is directed to a compound of the present invention or an individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof, for use in treating, inhibiting, or ameliorating arrhythmia, or maintaining normal sinus rhythm.
  • Another aspect of this invention is directed to a compound of the present invention or an individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof, for use in controlling heart rate.
  • alk refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, or 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t -butyl, pentyl, hexyl, heptyl, octyl, or any subset of the foregoing.
  • substituted alkyl refers to alkyl groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing.
  • groups such as by groups described above in the definition of R 10 , such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted),
  • alkenyl refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at least one double carbon to carbon bond (either cis or trans), such as ethenyl.
  • substituted alkenyl refers to alkenyl groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing.
  • alkynyl refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at least one triple carbon to carbon bond, such as ethynyl.
  • substituted alkynyl refers to alkynyl groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing.
  • aryl refers to aromatic homocyclic (i . e ., hydrocarbon) mono-, bi- or tricyclic ring-containing groups such as having 6 to 12 members such as phenyl, naphthyl and biphenyl. Phenyl is an example of an aryl group.
  • substituted aryl refers to aryl groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing, where optionally one or more pair of substituents together with the atoms to which they are bonded form a 3 to 7 member ring.
  • groups such as by groups described above in the definition of R 10 , such as selected from alkyl, substituted alkyl,
  • cycloalkyl refers to mono-, bi- or tri homocyclic ring groups of 3 to 15 carbon atoms which are, respectively, fully saturated and partially unsaturated.
  • the rings of multi-ring cycloalkyl groups may be fused, bridged and/or joined through one or more spiro unions.
  • substituted cycloalkyl refers to a cycloalkyl group substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, or any subset of the foregoing.
  • groups such as by groups described above in the definition of R 10 ), such as selected from aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alk
  • halogen and halo refer to fluorine, chlorine, bromine and iodine.
  • haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF 3 , having the specified number of carbon atoms, substituted with 1 or more halogen, up to and including perhalo alkyls (where all hydrogen atoms are replaced with a halogen).
  • heterocycle refers to fully saturated or partially or completely unsaturated, including aromatic (“heteroaryl”) or nonaromatic cyclic groups (for example, 3 to 13 ring member monocyclic, 7 to 17 ring member bicyclic, or 10 to 20 ring member tricyclic ring systems, such as, in certain embodiments, a monocyclic or bicyclic ring containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring.
  • aromatic heteroaryl
  • nonaromatic cyclic groups for example, 3 to 13 ring member monocyclic, 7 to 17 ring member bicyclic, or 10 to 20 ring member tricyclic ring systems, such as, in certain embodiments, a monocyclic or bicyclic ring containing a total of 3 to 10 ring atoms
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro unions.
  • Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyr
  • bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, benzodioxolyl, dihydrobenzodioxolyl, benzodioxinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydro
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • substituted heterocycle refers to heterocycle, heterocyclic and heterocyclo groups substituted with one or more groups (such as by groups described above in the definition of R 10 ), such as selected from alkyl, substituted alkyl, alkenyl, oxo, aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo (optionally substituted), halo, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), alkylester (optionally substituted), arylester (optionally substituted), cyano, nitro, amido, amino, substituted amino, lactam, urea, urethane, sulfonyl, or any subset of the foregoing, where optionally one or more pair of substitu
  • alkanoyl refers to alkyl group (which may be optionally substituted as described above) linked to a carbonyl group ( i . e ., -C(O)-alkyl).
  • aroyl refers to an aryl group (which may be optionally substituted as described above) linked to a carbonyl group ( i . e ., -C(O)-aryl).
  • salts may form salts or solvates which are also within the scope of this invention.
  • Reference to a compound described herein is understood to include reference to salts thereof, unless otherwise indicated.
  • zwitterions when a compound described herein contains both a basic moiety and an acidic moiety, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)" as used herein.
  • the salts are pharmaceutically acceptable ( i .
  • Salts of the compounds described herein may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the present invention is intended to cover the compounds in their neutral state, salts of those compounds, or mixtures of the compounds in their neutral state with one or more salt forms, or mixtures of salt forms.
  • the compounds described herein which contain a basic moiety may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates,
  • the compounds described herein which contain an acidic moiety may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t -butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e . g ., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates ( e . g ., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides ( e . g ., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides ( e . g ., benzyl and phenethyl bromides), and others.
  • agents such as lower alkyl halides (e . g ., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates ( e . g .
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio or which have otherwise been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • the various compounds described herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to isomers, such as enantiomers, diastereomers, and other stereoisomeric forms.
  • isomers such as enantiomers, diastereomers, and other stereoisomeric forms.
  • Such forms may be defined, in terms of absolute stereochemistry, as ( R )- or ( S )-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible individual stereoisomers and mixtures thereof, including their racemic and optically pure enantiomeric or diastereomeric forms.
  • the compounds may be prepared as racemates and can conveniently be used as such, or optically active (+) and (-), ( R )- and ( S )-, or (D)- and (L)-isomers or corresponding diastereomers may be prepared using chiral synthons or chiral reagents, or they may be resolved from racemic mixtures using conventional techniques, such as chiral chromatography or reverse phase HPLC.
  • optically active (+) and (-), ( R )- and ( S )-, or (D)- and (L)-isomers or corresponding diastereomers may be prepared using chiral synthons or chiral reagents, or they may be resolved from racemic mixtures using conventional techniques, such as chiral chromatography or reverse phase HPLC.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H or D and 3 H or T, carbon such as 11 C, 13 C, and 14 C, chlorine, such as 36 Cl, fluorine such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N oxygen, such as 15 O, 17 O, and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2 H or D, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • All stereoisomers of the present compounds such as those which may exist due to asymmetric carbons on the various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the present invention is intended to cover stable compounds.
  • any variable e . g ., R 13
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 13 at each occurrence is selected independently from the definition of R 13 .
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • “Therapeutically effective amount” refers to that amount of a compound which, when administered to a subject, is sufficient to effect treatment for a disease or disorder described herein.
  • the amount of a compound which constitutes a “therapeutically effective amount” will vary depending on the compound, the disorder and its severity, and the age of the subject to be treated, but can be determined routinely by one of ordinary skill in the art.
  • Treating covers the treatment, prophylaxis, and/or reducing the risk, of a disease or disorder described herein, or treatment, prophylaxis, or reducing the risk of a symptom of a disease or disorder, in a subject, such as a human, and includes:
  • Subject refers to a warm blooded animal such as a mammal, such as a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and disorders described herein.
  • the present invention provides compound of formula (I), or enantiomers, diastereomers, tautomers, salts or saturates thereof wherein:
  • the present invention provides compound of formula (I), or enantiomers, diastereomers, tautomers, salts or solvates thereof wherein:
  • the present invention provides compound of formula (Ia) or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or enantiomers, diastereomers, tautomers, salts or solvates thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or salts thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or salts thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or salts thereof, wherein:
  • the present invention provides compound of formula (I) or (Ia), or salts thereof, wherein:
  • compounds, enantiomers, diastereomers, tautomers, or salt thereof, of the present invention are selected from the compounds exemplified in the examples.
  • compositions comprising a therapeutically effective amount of at least one compound of formula (I), (Ia), and/or compounds exemplified in the examples.
  • compositions comprising a therapeutically effective amount of at least one compound of formula (I), (Ia), and/or compounds exemplified in the examples, and at least one other therapeutic agent, for example, anti-arrhythmic agents, calcium channel blockers, anti-platelet agents, anti-hypertensive agents, anti thrombotic/anti thrombolytic agents, anti coagulants, HMG-CoA reductase inhibitors, anti diabetic agents, thyroid mimetics, mineralocorticoid receptor antagonists, and cardiac glycosides, are provided.
  • anti-arrhythmic agents for example, anti-arrhythmic agents, calcium channel blockers, anti-platelet agents, anti-hypertensive agents, anti thrombotic/anti thrombolytic agents, anti coagulants, HMG-CoA reductase inhibitors, anti diabetic agents, thyroid mimetics, mineralocorticoid receptor antagonists, and cardiac glycosides.
  • compositions comprising a therapeutically effective amount of at least one compound of formula (I), (Ia), or compounds exemplified in the examples, and at least one other therapeutic agent, for example, sotalol, dofetilide, diltiazem, verapamil, clopidogrel, cangrelor, ticlopidine, CS-747, ifetroban, aspirin, a beta adrenergic blocker, an ACE inhibitor, an A II antagonist, an ET antagonist, a dual ET/A II antagonist, a vasopepsidase inhibitor, tPA, recombinant tPA, TNK, nPA, a factor VIIa inhibitor, a factor Xa inhibitor, a factor XIa inhibitor, a thrombin inhibitor, warfarin, a heparin, pravastatin, lovastatin, atorvastatin, simvastatin, NK-104, ZD-4522, a big
  • compositions comprising a therapeutically effective amount of at least one compound of formula (I), (Ia), or compounds exemplified in the examples, and at least one other therapeutic agent, for example, captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril, omapatrilat, gemopatrilat, and apixaban, are provided.
  • captopril zofenopril
  • fosinopril fosinopril
  • enalapril ceranopril
  • cilazopril delapril
  • pentopril quinapril
  • ramipril lisinopril
  • omapatrilat gemopatrilat
  • apixaban apixaban
  • a compound of formula (I), (Ia), or compound exemplified in the examples is provided for use in treating or preventing arrhythmia.
  • a compound of formula (I), (Ia), or compound exemplified in the examples is provided for use in treating or preventing supraventricular arrhythmia, for example, atrial fibrillation and atrial flutter.
  • a compound of formula (I), (Ia), or compound exemplified in the examples is provided for use in controlling heart rate.
  • a compound of formula (I), (Ia), or compound exemplified in the examples is provided for use in treating an I Kur -associated conditions, for example, gastrointestinal disorders, such as reflux esophagitis and a motility disorder; inflammatory and/or immunological diseases, such as chronic obstructive pulmonary disease; diabetes; cognitive disorders; migraines; epilepsy; and hypertension.
  • an I Kur -associated conditions for example, gastrointestinal disorders, such as reflux esophagitis and a motility disorder; inflammatory and/or immunological diseases, such as chronic obstructive pulmonary disease; diabetes; cognitive disorders; migraines; epilepsy; and hypertension.
  • compositions comprising a compound of the invention together with a pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutically acceptable carrier diluent, or excipient.
  • the composition optionally further comprises another pharmaceutically acceptable carrier or diluent and/or a pharmaceutically acceptable excipient.
  • Another aspect of this invention is directed to a compound of the present invention or an individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or disorders associated with inhibition of potassium channel function, wherein the disease or disorder is atrial fibrillation, controlling heart rate, and/or prophylactically treating arrhythmia.
  • the compounds of the invention may be useful in therapy.
  • the compounds of the invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of diseases or disorders associated with inhibition of potassium channel function, of the K v 1 subfamily of voltage gated K + channels, of K v 1.5 (which have been linked to the ultra-rapidly activating delayed rectifier K + current I Kur , and/or K v 1.3 channels, and/or K v 1.1 channels.
  • the compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).
  • the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
  • novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • the compounds of the present invention may be prepared by the exemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples. Protection and de-protection of functional groups in the processes below may be carried out by procedures generally known in the art (see, for example, Greene, T.W. et al., Protecting Groups in Organic Synthesis, Third Edition, Wiley (1999 ). General methods of organic synthesis and functional group transformations are found in: Trost, B.M.
  • novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
  • compounds of formula (I) can be synthesized by the general sequence shown in Scheme 2.
  • N-amino derivative 6 was treated with methylchloroformate and the resulting acyl derivative 9 was subjected to ring closure with ammonia under pressure to yield the pyrrolotriazine core 10.
  • Intermediate 10 was converted to the corresponding dichloro derivative 11 using chlorinating agents for example, phosphorous oxychloride. Sequential displacement of chloro of 11 at the 4 position followed by transition metal mediated cross coupling or displacement of the C2 chloride of 12 formed compounds of general formula (I).
  • compounds of formula (I) can be synthesized by the general sequence shown in Scheme 3.
  • Commercially available 5-methyl-3,4-dihydro-2H-pyrrole 13 was treated with N-chlorosuccinimide followed by sodium methoxide to generate methyl 3-chloro-1H-pyrrole-2-carboxylate 14.
  • Compound 14 was N-aminated and the product 15 was acylated to yield methyl 3-chloro-1-(methoxycarbonylamino)-1H-pyrrole-2-carboxylate 16.
  • Compound 16 was treated with ammonia to yield 5-chloropyrrolo[1,2-fl[1,2,4]triazine-2,4-diol 17.
  • Compound 10 can be obtained from 17 by transition metal mediated Suzuki cross-coupling reactions with boronic acids or esters.
  • Compound 17 gave 2,4,5-trichloropyrrolo[1,2-f][1,2,4]triazine 18 on treatment with chlorinating agents for example, POCl 3 and then displacement of the C4 chloro with amines gave regioselectively 19.
  • chlorinating agents for example, POCl 3
  • displacement of the C4 chloro with amines gave regioselectively 19.
  • Using different palladium reagent/ ligand combinations we could achieve regioselective Suzuki cross-couplings at C2 and C5 to generate compounds of general formula (I).
  • Preparative HPLC was carried on AGILENT® 1200 series, Shimadzu prominence or Waters systems.
  • Preparative SFC was performed on Thar instrument.
  • Reverse phase analytical HPLC/MS was performed on AGII,ENT® 1200 systems coupled with Mass Spectrometers.
  • LCMS was performed on AGILENT® 1200 or Waters AQUTTY® system coupled with Mass Spectrometer.
  • Chiral analytical LC was performed on a Thar Analytical SFC instrument.
  • 1 H NMR spectra were obtained with Bruker or JEOL® Fourier transform spectrometers operating at frequencies as follows: 1 H NMR: 400 MHz or 300 MHz (Bruker) 13 C NMR: 100 MHz or 75 MHz (Bruker). Spectra data are reported in the format: chemical shift (multiplicity, coupling constants, number of hydrogens).
  • Ammonium chloride (3.00 g, 56.1 mmol) was dissolved in ether (110 mL) and the solution cooled to -5 °C. Concentrated ammonium hydroxide (28.0 M, 4.70 mL, 120 mmol) was added dropwise. Commercial bleach that is sodium hypochorite (2M, 72.0 mL, 0.144 mol) was added via addition funnel over 15 min. The reaction mixture was stirred for 15 min, the layers were separated and the organic layer was washed with brine. The organic layer was dried over powdered CaCl 2 in a freezer for 1 h and stored at -40 °C. The approximate concentration of monochloramine is 0.15 M.
  • Methyl 3-phenyl-1-(5-sulfamoylnicotinamido)-1H-pyrrole-2-carboxylate (1.20 g, 4.30 mmol) was taken in a pressure tube and NH 4 OH (100 mL, 3.00 mol) solution was added. Then the reaction mixture was heated to 110 °C for 48 h. The reaction mixture was concentrated under reduced pressure to remove water and then azeotroped 3 times with toluene. The crude solid was triturated successively with ethyl acetate (5 mL) and methanol (2 mL).
  • Methyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate (0.200 g, 0.925 mmol) was dissolved in CH 2 Cl 2 (20 mL) and then was added TEA (0.387 mL, 2.77 mmol), followed by ethylchloroformate (0.0890 mL, 0.925 mmol). The reaction mixture was stirred at room temperature for overnight. Water (50 mL) was added to reaction mixture and the aqueous mixture was extracted with CH 2 Cl 2 (25x2 mL). The organic layer separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Methyl 1-((ethoxycarbonyl)amino)-3-phenyl-1H-pyrrole-2-carboxylate (1.00 g, 3.47 mmol) was taken in a pressure tube and ammonium hydroxide (30%, 67.5 mL, 1.73 mol) was added and sealed. The reaction mixture was stirred at 110 °C for 30 h and transferred to a round bottomed flask and concentrated under reduced pressure. Toluene was added to it and azeotroped to remove trace amount of water (3 times).
  • N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.597 mmol
  • 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine 0.263 g, 1.20 mmol, commercial
  • K 2 CO 3 0.248 g, 1.79 mmol
  • the reaction mixture was degassed with nitrogen for 15 minutes then PdCl 2 (dppf)-CH 2 Cl 2 (0.0490 g, 0.0600 mmol) was added.
  • Methyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate (0.400 g, 1.85 mmol) and 2-(N-( tert -butyl)sulfamoyl)thiazole-4-carboxylic acid (0.733 g, 2.77 mmol) ( Johnson et al., WO 2011/28741 ) were dissolved in DMF (10 mL) and cooled to 0 °C. HATU (1.41 g, 3.70 mmol) was added slowly, followed by DIPEA (1.29 mL, 7.40 mmol).
  • reaction mixture was allowed to reach ambient temperature over 14 h and was diluted with water (25 mL) and extracted with ethylacetate (3x20 mL). The organic layer was separated and the combined organic portions dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 38% EtOAc/hexanes) to afford methyl 1-(2-(N-( tert- butyl)sulfamoyl)thiazole-5-carboxamido)-3-phenyl-1H-pyrrole-2-carboxylate (0.250 g, 29.2%).
  • REDISEP® silica gel, 40 g, 38% EtOAc/hexanes
  • Methyl 1-(2-(N-( tert -butyl)sulfamoyl)thiazole-5-carboxamido)-3-phenyl-1H-pyrrole-2-carboxylate (0.250 g, 0.540 mmol) was dissolved in aqueous ammonium hydroxide (30 M, 5.00 mL, 0.150 mol) and heated to 100 °C in a sealed tube for 16 h. The reaction mixture was allowed to cool and evaporated under reduced pressure.
  • N-( tert -Butyl)-4-(4-hydroxy-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)thiazole-2-sulfonamide (0.0600 g, 0.140 mmol) was dissolved in acetonitrile (5 mL) and cooled to 0 °C.
  • BOP reagent (0.0620 g, 0.140 mmol) was added slowly, followed by DBU (0.0210 mL, 0.140 mmol). The reaction mixture was allowed to reach ambient temperature for 1 h then cooled to 0 °C.
  • Pyridin-2-ylmethanamine was added, (0.0150 g, 0.140 mmol).
  • reaction mixture was allowed to reach ambient temperature and stir for 14 h and diluted with water.
  • aqueous mixture was extracted with ethyl acetate (3x10 mL).
  • the combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure.
  • N-( tert -Butyl)-4-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)thiazole-2-sulfonamide (40.0 mg, 0.0770 mmol) and TFA (3 mL) were stirred at ambient temperature for 14 h.
  • Ammonium chloride (3.00 g, 60.0 mmol) was dissolved in ether (110 mL) and the solution cooled to -5 °C. Concentrated ammonium hydroxide (28 M, 4.70 mL, 120 mmol) was added dropwise. Commercial bleach that is sodium hypochorite (2M, 72.0 mL, 0.144 mol) was added via addition funnel over 15 min. The reaction mixture was stirred for 15 min, the layers were separated and the organic layer was washed with brine. The organic layer was dried over powdered CaCl 2 in a freezer for 1 h and stored at -40 °C. The approximate concentration of monochloramine is 0.15 M.
  • Methyl 3-chloro-1-((methoxycarbonyl)amino)-1H-pyrrole-2-carboxylate (5.00 g, 21.5 mmol) in MeOH (15 mL)/water (35 mL) was taken in a pressure tube and the reaction mixture was cooled to -80 °C. The reaction mixture was purged with NH 3 gas for 5-10 min. The pressure tube was closed and heated at 120 °C for 12 h. The solvents were removed under reduced pressure to give a brown solid which was recrystallized with MeOH to gave 5-chloropyrrolo[1,2-f][1,2,4]triazine-2,4-diol (2.65 g, 65.0%) as a white solid.
  • N-( tert -butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (1.37 g, 4.01 mmol)
  • K 2 CO 3 (1.11 g, 8.03 mmol)
  • 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.164 g, 0.201 mmol) at 110 °C for 14 h.
  • N-( tert -Butyl)-5-(5-phenyl-4-((1-phenylethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.500 g, 0.949 mmol) was converted to 5-(5-phenyl-4-((1-phenylethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide by following the procedure reported in Example 5 using TFA (0.366 mL, 4.75 mmol) at room temperature for 24 h.
  • Ent-1 5-(5-Phenyl-4-((1-phenylethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.0450 g, 10.1%).
  • Chiral HPLC Condition B-50 retention time 7.19 min, Purity 100.00%.
  • Ent-2 5-(5-Phenyl-4-((1-phenylethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.0650 g, 14.6%).
  • Chiral HPLC Condition B-50 retention time 9.79 min, Purity 99.70%.
  • N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (1.00 g, 32.9 mmol) (prepared as in Example 4) was converted to 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinonitrile via Suzuki cross-coupling using the conditions mentioned in Example 3.
  • N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.100 g, 0.299 mmol) was converted to ethyl 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinate via Suzuki cross-coupling using the conditions mentioned in Example 3.
  • N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.100 g, 0.299 mmol) (prepared as in Example 4), converted to N-benzyl-2-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine via Suzuki cross-coupling using the conditions mentioned in Example 3.
  • N-Benzyl-2-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.150 g, 0.314 mmol) was dissolved in TFA (10 mL) and stirred for 1 h at 60 °C. TFA was removed under reduced pressure and the reaction mixture was diluted with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (3x30 mL).
  • Ent-1 1-(5-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)ethane-1,2-diol (18.0 mg, 32.7%).
  • Chiral HPLC Condition B-52 retention time 5.39 min, Purity 98.32%.
  • Ent-2 1-(5-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)ethane-1,2-diol (20.0 mg, 36.4%).
  • Chiral HPLC Condition B-52 retention time 6.22 min, Purity 97.88%.
  • N-( tert -Butyl)-6-chloropyrazine-2-sulfonamide (0.500 g, 2.00 mmol) ( Johnson et al., WO 2011/28741 ) was converted to N-( tert -butyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-sulfonamide following the procedure as in Example 14 and by using bis(pinacolato)diboron (0.763 g, 3.00 mmol), KOAc (0.786 g, 8.01 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.164 g, 0.200 mmol) at 100 °C in a sealed tube for 14 h.
  • reaction mixture was allowed to cool, filtered through CELITE®, washed with dioxane.
  • the filtrate was evaporated under reduced pressure to get N-( tert -butyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-sulfonamide (0.500 g, 73.2%) which was used without further purification.
  • N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.300 g, 0.896 mmol) (prepared as in Example 4), was converted to 6-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-( tert -butyl)pyrazine-2-sulfonamide via Suzuki cross-coupling using the conditions mentioned in Example 3.
  • N-( tert -butyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-sulfonamide 0.306 g, 0.896 mmol
  • K 2 CO 3 0.248 g, 1.79 mmol
  • 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.0730 g, 0.0900 mmol) at 95 °C for 14 h.
  • 6-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-( tert- butyl)pyrazine-2-sulfonamide (0.0300 g, 0.0580 mmol) was converted to 6-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrazine-2-sulfonamide following the Example 5 by treating with TFA (2 mL) at ambient temperature.
  • N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.597 mmol) (prepared as in Example 4) was converted to 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-( tert- butyl)-2-((4-methoxybenzyl)oxy) pyridine-3-sulfonamide via Suzuki cross-coupling using the conditions mentioned in Example 3.
  • N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.300 g, 0.896 mmol) (as in Example 4) and 2,4,6-trivinyl cyclotriboroxane pyridine complex (0.323 g, 1.34 mmol) were dissolved in dioxane (15 mL) and then cesium carbonate (0.584 g, 1.79 mmol) dissolved in water (2 mL) was added. The reaction mixture was degassed with nitrogen for 15 minutes, then tetrakistriphenylphosphine palladium (0.0520 g, 0.0450 mmol) was added and the resulting reaction mixture degassed for 15 minutes.
  • N-Benzyl-5-phenyl-2-vinylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.150 g, 0.460 mmol) was dissolved in 3:1 ratio of dioxane (15 mL) and water (5 mL) and N-methylmorpholine N-oxide monohydrate (0.0620 g, 0.460 mmol) was added, followed by the addition of osmium tetroxide (0.0430 mL, 0.138 mmol).
  • the reaction mixture was stirred at room temperature for 14 h then filtered through a CELITE® bed and the filtrate was extracted by CH 2 Cl 2 (25x2 mL).
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the residue resolved into individual enantiomers by chiral HPLC (Condition B-52 as described in general methods).
  • Ent-1 1-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethane-1,2-diol (0.0250 g, 15.1%).
  • Chiral HPLC Condition B-52 retention time 5.05 min, Purity 99.10%.
  • Ent-2 1-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)ethane-1,2-diol (20.0 mg, 12.1%).
  • Chiral HPLC Condition B-52 retention time 6.10 min, Purity 98.10%.
  • N-Benzyl-2-chloro-5-phenylpyrrolo[1,2-f][1,2,4]triazin-4-amine (0.300 g, 0.900 mmol) (prepared as in Example 4) was converted to 5-(4-(benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinaldehyde via Suzuki cross-coupling using the conditions mentioned in Example 3.
  • Enantiomer-I 1-(5-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)ethanol (30.0 mg, 28.0%).
  • HPLC Condition B-6 retention time 13.61 min, Purity 96.13%.
  • Enantiomer-II 1-(5-(4-(Benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4] triazin-2-yl)pyridin-3-yl)ethanol (20.0 g, 25.0%).
  • HPLC Condition B-6 retention time 13.61 min, Purity 96.13%.
  • N-( tert -Butyl)-5-(5-phenyl-4-((2-(pyrazin-2-yloxy)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide 80.0 mg, 0.147 mmol was converted to 5-(5-phenyl-4-((2-(pyrazin-2-yloxy)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide using TFA (0.0210 mL, 0.278 mmol) as per the procedure in Example 5.
  • N-Benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (50.0 mg, 0.149 mmol) (prepared as in Example 4) was converted to N-benzyl-2-(5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridin-3-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine via Suzuki cross-coupling using the conditions mentioned in Example 3.
  • Residue obtained was purified by preparative HPLC (Condition B-73 as described in general methods) to get N-benzyl-2-(5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridin-3-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (25.0 mg, 34.1%).
  • 3,5-Dibromopyridine (3.00 g, 12.7 mmol) was dissolved in THF (20 mL) and the solution cooled to -20 °C.
  • Isopropyl magnesium chloride- lithium chloride complex (2.76 g, 19.0 mmol) was added to the solution under the nitrogen atmosphere.
  • the reaction mixture was stirred for 45 minutes and sulfuryl chloride (1.55 mL, 19.0 mmol) was added (at -20 °C). Stirring continued for additional 30 minutes and to this mixture was added THF (10 mL) solution containing ethylglycinate (7.07 g, 50.7 mmol) and DIPEA (11.1 mL, 63.3 mmol) at -20 °C.
  • Ethyl 2-(5-bromopyridine-3-sulfonamido)acetate (0.300 g, 0.928 mmol) was converted to ethyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamido)acetate following the general procedure described for Example 14 using bis(pinacolato)diboron (0.350 g, 1.39 mmol), KOAc (0.0910 g, 0.928 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.758 g, 0.928 mmol) in dioxane at 110 °C in a sealed tube for 14 h.
  • N-( tert -Butyl)-5-(4-((2-hydroxy-1-(pyridin-2-yl)ethyl)amino)-5-phenylpyrrolo [2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.300 g, 0.552 mmol) was converted to 5-(4-((2-hydroxy-1-(pyridin-2-yl)ethyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide using TFA (4.34 mL, 56.3 mmol) at room temperature for 12 h. The volatile components were removed under reduced pressure.
  • Enantiomer-2 LCMS Condition B-13: retention time 1.92 min, [M+1] 488.0.
  • HPLC Condition B-104 retention time 8.42 min, purity 97.85%.
  • N-( tert -Butyl)-2-(difluoromethyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino) pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.520 g, 0.923 mmol) was dissolved in CH 2 Cl 2 (4 mL). Then TFA (1.00mL, 13.0 mmol) was added and stirred at RT for 16 h. The volatile components were removed under reduced pressure and the resulting residue was diluted with 10% NaHCO 3 (25 mL). The reaction mixture was extracted with EtOAc (2x25 mL).
  • N-( tert -Butyl)-2-methoxy-5-(5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.180 g, 0.324 mmol) was dissolved in TFA (2.00 mL, 26.0 mmol) and heated at 70 °C for 2 h. The volatile components were removed under reduced pressure and resulting residue was diluted with saturated NaHCO 3 (30 mL). The reaction mixture was extracted with EtOAc (3x50 mL).
  • 6-Chloro-N-(4-methoxybenzyl)pyrazin-2-amine (5.00 g, 20.0 mmol) was dissolved in TFA (25 mL) and the reaction mixture heated for 2 h at 60 °C. TFA was removed under reduced pressure and reaction mixture was diluted with 10% sodium bicarbonate solution (100 mL) extracted with ethyl acetate (3x30 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by CombiFlash (REDISEP®, silica gel, 24 g, 35% EtOAc/petroleum ether) to give 6-chloropyrazin-2-amine (2.00 g, 77.0%).
  • REDISEP® silica gel, 24 g, 35% EtOAc/petroleum ether
  • reaction mixture was allowed to cool to RT and then 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.100 g, 0.298 mmol) was added followed by LiCl (13.0 mg, 0.298 mmol).
  • the reaction mixture was heated at 100 °C for 12 h.
  • the cooled reaction mixture was filtered through the CELITE® and washed with ethyl acetate (10 mL).
  • the resulting suspension was purged with N 2 gas for 5 minutes then heated at 100 °C in a sealed tube for 12 h.
  • the reaction mixture was allowed to cool to RT and water (10 mL) was added.
  • the reaction mixture was extracted with EtOAc (2x25 mL) and the combined organic extracts washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Methyl 2-(( tert -butoxycarbonyl)amino)-3-mercaptopropanoate (1.00 g, 4.25 mmol) was dissolved in DCM (15 mL) and cooled to 0 °C. Chlorine gas was purged (1 bladder) through the reaction mixture for 30 minutes and the reaction mixture stirred at room temperature for an additional 30 minutes. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2x100 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue.
  • Examples 47-185 were synthesized via the procedures described above for Examples 1-46. HPLC/MS data for each compound was collected using method mentioned in the table, and the molecular mass determined by MS(ES) by the formula m / z. The retention time, MS, and proton NMR data for Examples 47-185 are listed in Table 1. Table 1 Ex. No.

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Claims (15)

  1. Verbindung der Formel (I)
    Figure imgb0368
     oder ein Enantiomer, Diastereomer, Tautomer, Salz oder Solvat davon, wobei:
    A -(CH2)m-R2, -CH(R26)-R2, -(CH2)n-1-O-R2, -(CH2)n-1-NR25-R2, CH(R26)CO2-R2 oder -(CH2)n-1-NR25-CO2-R2 ist;
    sich A und R24, zusammen mit dem Stickstoff, an den sie gebunden sind, kombinieren, um
    Figure imgb0369
     zu bilden, wobei jedes davon mit 0-2 R2a substituiert werden kann;
    R1 C1-10-Alkyl substituiert mit 1-2-OH, Halo-C1-10-Alkyl, C2-12-Alkenyl oder C3-10-Cycloalkyl ist, wobei das Cycloalkyl mit 0-2 R13 substituiert werden kann; oder
    R1
    Figure imgb0370
    Figure imgb0371
    Figure imgb0372
     oder
    Figure imgb0373
     ist, wobei jedes davon mit 0-2 R13 substituiert werden kann; oder R1-C(O)-R1a ist;
    R1a -NH-Phenyl, -NH-C1-6-Alkyl-phenyl, -NH-C3-6-Cycloalkyl, -Piperidinyl, Piperazinyl oder -NH-Pyrimidinyl ist, wobei das Phenyl, Alkyl, Cycloalkyl, Piperidinyl, Piperazinyl oder Pyrimidinyl mit 0-2 R13 substituiert werden kann;
    R2 Phenyl, Cyclopentyl, Cyclohexyl, Pyridinyl, Pyrazinyl, Pyridazinyl, Pyrimidinyl, Piperidinyl, Pyridinon, Pyrrolidinyl, Tetrahydropyranyl, Thiazolyl, Imidazolyl, Isoxazolyl, Oxazolyl, Morpholinyl, Benzothiazolyl oder Tetrahydronaphthalenyl ist, wobei jedes davon mit 0-2 R2a substituiert werden kann;
    R2a bei jedem Vorkommen unabhängig H, -OH, F, Cl, Br, I, C1-10-Alkyl, C1-10-Alkoxy, Halo-C1-10-Alkyl, C3-10-Cycloalkyl, C2-12-Alkenyl, C2-12-Alkynyl, C6-10-Aryl, ein 4- bis 12-gliedriges Heteroaryl, ein 4- bis 12-gliedriges Heterocyclyl, ein 4- bis 12-gliedriges Heteroaryl-C1-10-alkyl, -CN, -NO2, -(CH2)m-SO2R14, -NR14SO2R14, =O, CONR14R14, (CH2)mSO2NR14R14, -(CH2)m-NR14SO2R14, (CH2)nNR14SO2NR14R14, NR14SO2NR14R14, -CO2NR14R14, -NR14CO2NR14R14, NR14COR14, -SO2NR14COR14, -SO2NR14CONR14R14, -NR14CO2R14, -CO2R14, NR14R14, -NR14CONR14R14, C(=NOR14)NR14R14, -CONR14OR14 oder -NCOR14 ist, wobei das Alkyl, Cycloalkyl, Alkenyl, Alkoxy, Aryl, Heteroaryl und Heterocyclyl mit 0-2 R14a substituiert werden können und das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen;
    R3 Phenyl, Pyridinyl, Pyrimidinyl, Dihydropyran oder Tetrahydropyran ist, wobei jedes davon mit 0-1 R3a substituiert werden kann;
    R3a Halo, CN, NH2, -O-C1-3-Alkyl oder Morpholinyl ist;
    R13 bei jedem Vorkommen unabhängig H, -OH, F, Cl, Br, I, CN, C1-10-Alkyl, C1-10-Alkoxy, Halo-C1-10-Alkyl, C3-10-Cycloalkyl, C2-12-Alkenyl, C2-12-Alkynyl, C6-10-Aryl, ein 4- bis 12-gliedriges Heteroaryl, ein 4- bis 12-gliedriges Heterocyclyl, ein 4- bis 12-gliedriges Heteroaryl-C1-10-alkyl, -CN, -NO2, -(CH2)mSO2R14, -NR14SO2R14, =O, CONR14R14, (CH2)m-SO2NR14R14, -(CH2)m-NR14SO2R14, -(CH2)n-NR14SO2NR14R14, NR14SO2NR14R14, -CO2NR14R14, -NR14CO2NR14R14, NR14COR14 , SO2NR14COR14, -SO2NR14CONR14R14, -NR14CO2R14, -CO2R14, NR14R14, NR14CONR14R14, NR14-CO-CO-NR14R14, C(=NOR14)NR14R14, -CONR14OR14, -NCOR14 oder OR14 ist, wobei das Alkyl, Cycloalkyl, Alkenyl, Alkoxy, Aryl, Heteroaryl und Heterocyclyl mit 0-2 R14a substituiert werden können und das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen; oder
    R13 SO2NHP(O)(OH)2 ist;
    R14 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-10-Alkyl, C3-10-Cycloalkyl, C6-10-Aryl, einem 4- bis 12-gliedrigen Heteroaryl oder einem 4- bis 12-gliedrigen Heterocyclyl ausgewählt ist, wobei das Alkyl, Cycloalkyl, Aryl, Heteroaryl und Heterocyclyl mit 0-3 R14a substituiert werden können und das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen; oder
    alternativ zwei R14s zusammengenommen sind mit den Atomen, an die sie angehängt sind, um einen cyclischen Ring zu bilden, wobei der cyclische Ring mit 0-1 R14a substituiert werden und optional 1, 2, 3 oder 4 Heteroatome, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, enthalten kann;
    R14a bei jedem Vorkommen unabhängig aus F, Cl, Br, I, C1-10-Alkyl, Halo-C1-10-Alkyl, C6-10-Aryl, C3-10-Cycloalkyl, einem 4- bis 12-gliedrigen Heteroaryl, einem 4- bis 12-gliedrigen Heterocyclyl, -CN, -NO2, -CO2R26, -CO2NR24R24, OCF3, -OR25, =O, -CONR24R24, -COR24, -SO2R24, -NR24R24, -NR24CO2R24, SO2NR24R24 oder C6-10-Aryl-C1-10-Alkyl ausgewählt ist, wobei das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen;
    R24 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-10-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist;
    R25 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-10-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist;
    R26 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-10-Alkyl, C1-10-Alkyl-OH, C1-6-Haloalkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist;
    m 0 bis 4 ist;
    n 0 bis 4 ist; und
    n-1 2 bis 4 ist.
  2. Verbindung der Formel (I)
    Figure imgb0374
     oder ein Enantiomer, Diastereomer, Tautomer, Salz oder Solvat davon, wobei:
    A -(CH2)m-R2, -CH(R26)-R2, -(CH2)n-1-O-R2, -(CH2)n-1-NR25-R2, -CH(R26)-CO2-R2 oder -(CH2)n-1-NR25-CO2-R2 ist;
    R1 C1-10-Alkyl substituiert mit 1-2-OH, Halo-C1-10-Alkyl, C2-12-Alkenyl oder C3-10-Cycloalkyl ist, wobei das Cycloalkyl mit 0-2 R13 substituiert werden kann; oder
    R1 ist
    R1
    Figure imgb0375
    Figure imgb0376
    Figure imgb0377
     order
    Figure imgb0378
     ist, wobei jedes davon mit 0-2 R13 substituiert werden kann;
    R2 Phenyl, Cyclopentyl, Cyclohexyl, Pyridinyl, Pyrazinyl, Pyridazinyl, Pyrimidinyl, Piperidinyl, Pyridinon, Pyrrolidinyl, Tetrahydropyranyl oder Thiazolyl ist, wobei jedes davon mit 0-2 R2a substituiert werden kann;
    R2a bei jedem Vorkommen unabhängig H, -OH, F, Cl, Br, I, C1-10-Alkyl, C1-10-Alkoxy, Halo-C1-10-Alkyl, C3-10-Cycloalkyl, C2-12-Alkenyl, C2-12-Alkynyl, C6-10-Aryl, ein 4- bis 12-gliedriges Heteroaryl, ein 4- bis 12-gliedriges Heterocyclyl, ein 4- bis 12-gliedriges Heteroaryl-C1-10-Alkyl, -CN, -NO2, -(CH2)m-SO2R14, -NR14SO2R14, =O, -CONR14R14, -(CH2)m-SO2NR14R14, -(CH2)m-NR14SO2R14, -(CH2)n-NR14SO2NR14R14, -NR14SO2NR14R14, -CO2NR14R14, -NR14CO2NR14R14, -NR14COR14, -SO2NR14COR14,-SO2NR14CONR14R14, -NR14CO2R14, -CO2R14, -NR14R14, -NR14CONR14R14, -C(=NOR14)NR14R14, -CONR14OR14 oder -NCOR14 ist, wobei das Alkyl, Cycloalkyl, Alkenyl, Alkoxy, Aryl, Heteroaryl und Heterocyclyl mit 0-2 R14a substituiert werden können und das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen;
    R3 Phenyl, Pyridinyl, Pyrimidinyl, Dihydropyran oder Tetrahydropyran ist, wobei jedes davon mit 0-1 R3a substituiert werden kann;
    R3a Halo, CN, NH2, -O-C1-3-Alkyl oder Morpholinyl ist;
    R13 bei jedem Vorkommen unabhängig H, -OH, F, Cl, Br, I, CN, C1-10-Alkyl, C1-10-Alkoxy, Halo-C1-10-Alkyl, C3-10-Cycloalkyl, C2-12-Alkenyl, C2-12-Alkynyl, C6-10-Aryl, ein 4- bis 12-gliedriges Heteroaryl, ein 4- bis 12-gliedriges Heterocyclyl, ein 4- bis 12-gliedriges Heteroaryl-C1-10-alkyl, -CN, -NO2, -(CH2)m-SO2R14, -NR14SO2R14, =O, -CONR14R14, -(CH2)m-SO2NR14R14, -(CH2)m-NR14SO2R14, -(CH2)n-NR14SO2NR14R14, -NR14SO2NR14R14, -CO2NR14R14, -NR14CO2NR14R14, -NR14COR14, -SO2NR14COR14, -SO2NR14CONR14R14, -NR14CO2R14, -CO2R14, -NR14R14, -NR14CONR14R14,-C(=NOR14)NR14R14, -CONR14OR14, -NCOR14 oder OR14 ist, wobei das Alkyl, Cycloalkyl, Alkenyl, Alkoxy, Aryl, Heteroaryl und Heterocyclyl mit 0-2 R14a substituiert werden können und das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen;
    R14 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-10-Alkyl, C3-10-Cycloalkyl, C6-10-Aryl, einem 4- bis 12-gliedrigen Heteroaryl oder einem 4- bis 12-gliedrigen Heterocyclyl ausgewählt ist, wobei das Alkyl, Cycloalkyl, Aryl, Heteroaryl und Heterocyclyl mit 0-3 R14a substituiert werden können und das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen; oder
    alternativ zwei R14s zusammengenommen sind mit den Atomen, an die sie angehängt sind, um einen cyclischen Ring zu bilden, wobei der cyclische Ring mit 0-1 R14a substituiert werden und optional 1, 2, 3 oder 4 Heteroatome, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, enthalten kann;
    R14a bei jedem Vorkommen unabhängig aus F, Cl, Br, I, C1-10-Alkyl, Halo-C1-10-Alkyl, C6-10-Aryl, C3-10-Cycloalkyl, einem 4- to 12-gliedrigen Heteroaryl, einem 4- bis 12-gliedrigen Heterocyclyl, -CN, -NO2, -CO2R26, -CO2NR24R24, -OCF3, -OR25, =O, -CONR24R24, -COR24, -SO2R24, -NR24R24, -NR24CO2R24, -SO2NR24R24 oder C6-10-ArylC1-10-alkyl ausgewählt ist, wobei das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen;
    R24 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-10-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist;
    R25 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-10-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist;
    R26 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-10-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist;
    m 0 bis 4 ist;
    n 0 bis 4 ist; und
    n-1 2 bis 4 ist.
  3. Verbindung nach den Ansprüchen 1-2, oder Salz davon, wobei:
    eines von R1 C1-10-Alkyl substituiert mit 1-2-OH, Halo-C1-10-Alkyl oder C3-10-Cycloalkyl ist, wobei das Cycloalkyl mit 0-2 R13 substituiert sein kann; oder
    Figure imgb0379
    Figure imgb0380
     wobei jedes davon mit 0-2 R13 substituiert sein kann.
  4. Verbindung nach den Ansprüchen 1-3, oder Salz davon, wobei:
    R13 bei jedem Vorkommen unabhängig H, -OH, F, Cl, Br, I, C1-6-Alkyl, C1-6-Alkoxy, Halo-C1-6 -Alkyl, C3-6-Cycloalkyl, Phenyl oder ein 4- bis 12-gliedriges Heteroaryl ist, wobei das Heteroaryl aus Tetrazolyl, -CN, -NO2, -(CH2)m-SO2R14, -NR14SO2R14, -CONR14R14, -(CH2)m-SO2NR14R14, -NR14CO2NR14R14, -NR14CO2NR14bR14b, -NR14COR14, -NR14CO2R14, -CO2R14 oder -NR14R14 ausgewählt ist, wobei das Alkyl, Cycloalkyl, Phenyl und Heteroaryl mit 0-2 R14a substituiert werden können und das Heteroaryl und Heterocyclyl aus Kohlenstoffatomen und 1, 2, 3 oder 4 Heteroatomen, die unabhängig aus der Gruppe ausgewählt sind, die aus N, S oder O besteht, bestehen;
    R14 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist, wobei das Alkyl, Cycloalkyl und Phenyl mit 0-3 R14a substituiert werden können;
    zwei R14bs zusammengenommen sind mit den Atomen, an die sie angehängt sind, um einen cyclischen Ring zu bilden, wobei der cyclische Ring Morpholinyl, Piperidinyl oder Piperazinyl ist und mit 0-1 C1-6-Alkyl substituiert werden kann; und
    R14a bei jedem Vorkommen unabhängig aus F, Cl, Br, I, C1-6-Alkyl, Halo-C1-6-Alkyl, Phenyl oder C3-6-Cycloalkyl ausgewählt ist.
  5. Verbindung nach den Ansprüchen 1-4, oder Salz davon, wobei:
    A -(CH2)m-R2, -CH(R26)-R2, -(CH2)n-1-O-R2, -(CH2)n-1-NR25-R2, -CH(R26)-CO2-R2 oder -(CH2)n-1-NR25-CO2-R2 ist;
    R2 Phenyl, Pyridinyl, Pyrazinyl, Pyrimidinyl, Piperidinyl oder Pyridinon ist, wobei jedes davon mit 0-2 R2a substituiert werden kann; und
    R2a bei jedem Vorkommen unabhängig H, -OH, F, C1-6-Alkyl, C1-6-Alkoxy oder 6-SO2NR14R14 ist.
  6. Verbindung nach den Ansprüchen 1-5, oder Salz davon, wobei:
    R1 C1-10-Alkyl substituiert mit 1-2 -OH, Halo-C1-10-Alkyl oder C3-10-Cycloalkyl ist, wobei das Cycloalkyl mit 0-1 R13 substituiert werden kann; oder
    R1
    Figure imgb0381
     ist, wobei jedes davon mit 0-2 R13 substituiert werden kann.
  7. Verbindung nach den Ansprüchen 1-6, oder Salz davon, wobei:
    R13 bei jedem Vorkommen unabhängig H, C1-6-Alkyl oder ein 4- bis 12-gliedriges Heteroaryl ist, wobei das Heteroaryl aus Tetrazolyl, -CN, -NR14SO2R14, -CONR14R14, -SO2NR14R14, -NR14CO2NR14R14, -NR14CO2NR14bR14b, -NR14COR14, -CO2R14 oder -NR14R14 ausgewählt ist, wobei das Alkyl und Heteroaryl mit 0-2 R14a substituiert werden können;
    R14 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist, wobei das Alkyl, Cycloalkyl und Phenyl mit 0-3 R14a substituiert werden können;
    zwei R14bs zusammengenommen sind mit den Atomen, an die sie angehängt sind, um einen cyclischen Ring zu bilden, wobei der cyclische Ring Morpholinyl ist und mit 0-1 C1-6-Alkyl substituiert werden kann; und
    R14a bei jedem Vorkommen unabhängig aus F, Cl, Br, I, C1-6-Alkyl, Halo-C1-6-Alkyl, Phenyl oder C3-6-Cycloalkyl ausgewählt ist.
  8. Verbindung nach den Ansprüchen 1-7, oder Salz davon, wobei:
    A -(CH2)-R2 ist;
    R2 Phenyl,
    Figure imgb0382
     ist, wobei jedes davon mit 0-1 R2a substituiert werden kann; und
    R2a bei jedem Vorkommen unabhängig H, -OH, F, C1-6-Alkyl, C1-6-Alkoxy, C1-6-Haloalkoxy oder SO2NR14R14 ist.
  9. Verbindung nach den Ansprüchen 1-8, wobei:
    R3 Phenyl ist.
  10. Verbindung nach den Ansprüchen 1-9, oder Salz davon, wobei:
    R24 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist;
    R25 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist; und
    R26 bei jedem Vorkommen unabhängig aus Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl oder Phenyl ausgewählt ist.
  11. Verbindung nach einem der Ansprüche 4 oder 7, oder Salz davon, wobei:
    R13 bei jedem Vorkommen unabhängig H, -CN, -NHSO2R14, -CONH2, -SO2NR14R14, -NHCO2NR14bR14b, -NHCOR14 oder -NH2 ist; und
    R14 bei jedem Vorkommen unabhängig aus Wasserstoff oder Methyl ausgewählt ist.
  12. Verbindung, Enantiomer, Diastereomer oder Salz davon, ausgewählt aus 5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    N-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)methansulfonamid;
    N1-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)malonamid;
    4-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)thiazol-2-sulfonamid;
    5-(5-(4-Fluorphenyl)-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2,5-Bis(6-methoxypyridin-3-yl)-N-(pyridin-2-ylmethyl)pyrrolo[1,2-f][1,2,4]triazin-4-amin;
    5-(5-Phenyl-4-(1-phenylethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinamid;
    5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinsäure;
    2-(5-(1H-Tetrazol-5-yl)pyridin-3-yl)-N-benzyl-5-phenylpyrrolo[1,2-f][,2,4]triazin-4-amin;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinsäure;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinamid;
    1-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2- f][1,2,4]triazin-2-yl)pyridin-3-yl)ethan-1,2-diol;
    6-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrazin-2-sulfonamid;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)-2-hydroxypyridin-3-sulfonamid,
    2-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)propan-2-ol;
    1-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)ethan-1,2-diol;
    3-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)propionsäure;
    (5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)methanol;
    1-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)ethanol;
    Methyl 1-(5-(4-(benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinoyl)pyrrolidin-2-carboxylat;
    5-(5-Phenyl-4-((2-(pyrazin-2-yloxy)ethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)propan-1,3-diol;
    1-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)urea;
    N-(4-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)phenyl)acetamid;
    4-(Benzylamino)-N-(3-(methylsulfonamido)phenyl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    2-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamido)acetamid;
    N1-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)succinamid;
    N1-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)oxalamid;
    5-(4-((2-MethylthiazoL-4-yl)methylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((2-Hydroxy-1-(pyridin-2-yl)ethyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    tert-Butyl 1-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)cyclopropylcarbamat;
    Methyl 1-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)cyclopropylcarbamat;
    N-(1-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)cyclopropyl)acetamid;
    N-(1-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)cyclopropyl)methansulfonamid;
    2-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][[1,2,4]triazin-2-yl)pyridin-3-yl)ethansulfonamid;
    2-(Difluormethyl)-5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-Methoxy-5-(5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-Isopropoxy-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    N-(6-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrazin-2-yl)acetamid;
    (±)-2-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)cyclopropancarbonitril;
    (±)-2-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)cyclopropancarboxamid;
    Methyl 2-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinamido)-3-sulfamoylpropanoat;
    ((5-(5-Phenyl-4-((pyrimidin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidinsäure;
    N-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2- f][1,2,4]triazin-2-yl)pyridin-3-yl)acetamid;
    N-(3-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)phenyl)acetamid;
    2-Hydroxy-5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    1-(3-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)phenyl)sulfonylurea;
    Ethyl 2-(N-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)sulfamoyl)acetat;
    N1-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)malonamid;
    N-(2-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)phenyl)acetamid;
    N-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2- f][1,2,4]triazin-2-yl)pyridin-2-yl)acetamid;
    2-(N-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4] triazin-2-yl)pyridin-3-yl)sulfamoyl)acetamid;
    N-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)cyclopropansulfonamid;
    N-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)propan-1-sulfonamid;
    2-Methyl-N-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)propan-1-sulfonamid;
    Ethyl 5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-ylcarbamat;
    Ethyl 2-(N-(3-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)phenyl)sulfamoyl)acetat;
    2,2,2-Trifluor-N-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4 ]triazin-2-yl)pyridin-3- yl)ethansulfonamid;
    N-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2- f][1,2,4]triazin-2-yl)pyridin-3-yl)ethansulfonamid;
    3-Chlor-N-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)propan-1-sulfonamid;
    N-(5-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2- f][1,2,4]triazin-2-yl)pyridin-3-yl)propan-2-sulfonamid;
    5-Phenyl-2-(1H-pyrazol-4-yl)-N-(pyridin-2-ylmethyl)pyrrolo[1,2-f][1,2,4]triazin-4-amin;
    3-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)benzonitril;
    4-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)benzonitril;
    5,5'-(4-(Pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-,5-diyl)dipyridin-3-amin;
    3-(2-(5-Aminopyridin-3-yl)-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-5-yl)benzonitril;
    2-(5-Aminopyridin-3-yl)-5-(6-methoxypyridin-3-yl)-N-(pyridin-2-ylmethyl)pyrrolo[1,2-f][1,2,4]triazin-4-amin;
    2-(5-Amino-6-methylpyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[1,2-f][1,2,4]triazin-4-amin;
    Isopropyl 5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-ylcarbamat;
    2-(5-Aminopyridin-3-yl)-N-(cyclohexylmethyl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-4-amin;
    N-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)methansulfonamid;
    N-(5-(4-(Cyclohexylmethylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)methansulfonamid;
    5-(4-(1-(4-Fluorphenyl)ethylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(1-(4-Fluorphenyl)ethylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    3-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-ylamino)-3-oxopropionsäure;
    5-(4-(2,6-Difluorbenzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(-Benzylamino)-5-phenylpyrrolo[1,2- f][1,2,4]triazin-2-yl)picolinonitril;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)picolinamid;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)picolinsäure;
    5-(5-Phenyl-4-(2,2,2-trifluor-1-phenylethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    (5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)(morpholino)methanon;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-(2-methoxyethyl)nicotinamid;
    Methyl 3-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)benzoat;
    3-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)benzoesäure;
    5-(5-Phenyl-4-(-2-,2,2-trifluor-1-phenylethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinonitril;
    Ethyl 3-(5-(4-(benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinamido)propanoat;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)nicotinamid;
    N-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-ylsulfonyl)acetamid;
    4-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)picolinonitril;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-tert-butyl-2-methoxypyridin-3-sulfonamid;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)-2-methoxypyridin-3-sulfonamid,
    4-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)picolinsäure;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-(2,3-dihydroxypropyl)nicotinamid;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-(2,3-dihydroxypropyl)nicotinamid;
    3-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)nicotinamido)propionsäure;
    (E)-3-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)acrylsäure;
    N-Benzyl-2-(3,6-dihydro-2H-pyran-4-yl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-4-amin;
    5-(5-Phenyl-4-((tetrahydro-2H-pyran-2-yl)methylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-Phenyl-4-((tetrahydro-2H-pyran-2-yl)methylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)-N,N-bis(2-hydroxyethyl)nicotinamid;
    5-(5-(3-Fluorphenyl)-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-(4-Methoxyphenyl)-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][[1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-(4-Morpholinophenyl)-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-(-4-Cyanophenyl)-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-Phenyl-4-(pyridazin-3-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    3-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][[1,2,4]triazin-2-yl)benzamid
    N-(5-(5-(4-Fluorphenyl)-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-yl)methansulfonamid;
    2-(6-Methoxypyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[1,2-f][1,2,4]triazin-4-amin;
    4-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)benzamid;
    N-(4-Acetamidophenyl)-4-(benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    4-(Benzylamino)-N-(2-carbamoylphenyl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    4-(Benzylamino)-N-(4-carbamoylphenyl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    4-(Benzylamino)-5-phenyl-N-(3-sulfamoylphenyl)pyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    4-(Benzylamino)-5-phenyl-N-(4-sulfamoylphenethyl)pyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    4-(Benzylamino)-N-(1-(hydroxymethyl)cyclopentyl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    (R)-4-(Benzylamino)-N-(2-hydroxy-2-phenylethyl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    (4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)(4-(4-hydroxyphenyl)piperazin-1-yl)methanon;
    1-(1-(4-(Benzylamino)-5 -phenylpyrrolo[1,2-f][1,2,4]triazin-2-carbonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-on;
    4-(Benzylamino)-N-(4-(2-hydroxyethyl)phenyl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    N-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-4-(benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    4-(Benzylamino)-5-phenyl-N-(pyrimidin-4-yl)pyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    4-(Benzylamino)-N-(2,4-dimethoxybenzyl)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-carboxamid;
    5-Phenyl-2-(1H-pyrazol-3-yl)-N-(pyridin-2-ylmethyl)pyrrolo[1,2-f][1,2,4]triazin-4-amin;
    6-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyrazin-2-sulfonamid;
    N-Benzyl-5-phenyl-2-(tetrahydro-2H-pyran-4-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amin;
    5-(4-(Benzylamino)-5-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-Amino-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((Cyclohexylmethyl)amino)-5-phenylpyrrolo[2,1- f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(((3-Fluorpyridin-2-yl)methyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-methoxypyridin-3-sulfonamid;
    2-Methoxy-5-(5-phenyl-4-((pyrimidin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-Ethoxy-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((Pyridin-2-ylmethyl)amino)-5-(2-(trifluormethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-(2-Chlorphenyl)-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-Methoxy-5-(5-phenyl-4-((pyrazin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(((3-Fluorpyridin-2-yl)methyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-Methoxy-5-(4-(((6-methoxypyridin-2-yl)methyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(((6-Methoxypyridin-2-yl)methyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((2-Cyano-6-fluorbenzyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((Oxazol-4-ylmethyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(Isoindolin-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((1-Hydroxycyclohexyl)methylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((1H-Imidazol-2-yl)methylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-Methoxy-5-(5-phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(Pyridin-2-ylmethylamino)-5-(pyridin-3-yl)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    3-(4-(Benzylamino)-5-phenylpyrrolo[1,2-f][1,2,4]triazin-2-yl)benzolsulfonamid;
    3-(5-Phenyl-4-(pyridin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)benzolsulfonamid;
    5-(5-Phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-2-ol;
    5-(5-Phenyl-4-((pyrimidin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    6-Hydroxy-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    6-(5-Phenyl-4-((pyrazin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrazin-2-sulfonamid;
    5-(4-((2-Morpholinoethyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-(2-Fluorphenyl)-4-((pyrazin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    4-(5-Phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-2-ol;
    5-(5-Phenyl-4-(pyridin-3 -ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid,
    3-(5-Phenyl-4-(pyridin-4-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)benzolsulfonamid;
    5-(5-Phenyl-4-(pyrazin-2-ylmethylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyrazin-2-ylmethyl)pyrrolo[1,2-f][1,2,4]triazin-4-amin;
    2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyrimidin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amin;
    5-(5-Phenyl-4-((thiazol-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((Oxazol-4-ylmethyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-Phenyl-4-((pyrimidin-4-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-(2-Fluorphenyl)-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    Methyl 2-(((5-phenyl-2-(5-sulfamoylpyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)methyl)benzoat;
    5-(4-((2-Cyanobenzyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-(((5-Phenyl-2-(5-sulfamoylpyridin-3-yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)amino)methyl)benzamid;
    5-(5-Phenyl-4-((5,6,7,8-tetrahydroquinolin-8-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-Phenyl-4-((5,6,7,8-tetrahydroquinolin-8-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((Benzo[d]thiazol-2-ylmethyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-(2-Fluorphenyl)-4-(((3-fluorpyridin-2-yl)methyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(((4-Methylthiazol-2-yl)methyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    2-Methoxy-5-(4-(((4-methylthiazol-2-yl)methyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-(((5-Methylisoxazol-3-yl)methyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    Ethyl 3-oxo-3-((5-(5-phenyl-4-((pyrazin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)amino)propanoat;
    5-(4-((2-Aminobenzyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(4-((2-(Methylsulfonamido)benzyl)amino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    N-(2-(((5-Phenyl-2-(5-sulfamoylpyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)methyl)phenyl)acetamid;
    Methyl (2-(((5-phenyl-2-(5-sulfamoylpyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)methyl)phenyl)carbamat;
    4-(Difluormethyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid;
    5-(5-Phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-2-sulfonamid;
    5-(5-(2-Cyanophenyl)-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-sulfonamid; und
    5-(5-Phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-ylsulfonylphosphoramidinsäure.
  13. Pharmazeutische Zusammensetzung, umfassend eine therapeutisch wirksame Menge mindestens einer Verbindung nach einem der Ansprüche 1 bis 12.
  14. Pharmazeutische Zusammensetzung nach Anspruch 13, weiter umfassend mindestens einen zusätzlichen therapeutischen Stoff.
  15. Verbindung nach einem der Ansprüche 1 bis 12 zur Verwendung bei der Behandlung von Arrhythmie oder beim Kontrollieren der Herzfrequenz.
EP14713005.8A 2013-03-11 2014-03-10 Pyrrolotriazine als kaliumionenkanalhemmer Not-in-force EP2970296B1 (de)

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Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20180815T8 (hr) * 2012-06-11 2019-02-08 Bristol-Myers Squibb Company Prolijekovi fosforamidne kiseline 5-[5-fenil-4-(piridin-2-ilmetilamino)hinazolin-2-il]piridin-3-sulfonamida
JP6386527B2 (ja) 2013-03-11 2018-09-05 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ カリウムイオンチャネル阻害剤としてのピロロピリダジン
WO2014143606A1 (en) 2013-03-11 2014-09-18 Bristol-Myers Squibb Company Pyrrolotriazines as potassium ion channel inhibitors
JP2016516691A (ja) 2013-03-11 2016-06-09 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ カリウムイオンチャネル阻害剤としてのイソキノリン
WO2017004134A1 (en) * 2015-06-29 2017-01-05 Nimbus Iris, Inc. Irak inhibitors and uses thereof
EP3344631A1 (de) * 2015-08-31 2018-07-11 Bristol-Myers Squibb Company Tgf-beta-rezeptor-antagonisten
CN105111154A (zh) * 2015-09-15 2015-12-02 上海瑞博化学有限公司 一种5-氨基吡嗪-2-甲酸合成新工艺
EP3394056B1 (de) 2015-12-22 2021-04-14 Shy Therapeutics LLC Verbindungen zur behandlung von krebs und entzündungskrankheiten
MD3436461T2 (ro) 2016-03-28 2024-05-31 Incyte Corp Compuși pirolotriazină ca inhibitori TAM
HUE059954T2 (hu) * 2016-04-28 2023-01-28 Takeda Pharmaceuticals Co Kondenzált heterociklusos vegyület
US10780068B2 (en) 2017-05-05 2020-09-22 Nino Sorgente Methods and compositions for improving eye health
US11382881B2 (en) 2017-05-05 2022-07-12 Nino Sorgente Methods and compositions for diagnosing and treating glaucoma
MA49458A (fr) 2017-06-21 2020-04-29 SHY Therapeutics LLC Composés interagissant avec la superfamille ras destinés à être utilisés dans le traitement de cancers, de maladies inflammatoires, de rasopathies et de maladies fibrotiques
CN111825675B (zh) * 2019-04-15 2023-08-01 武汉朗来科技发展有限公司 Rock抑制剂及其制备方法和用途
CN116745288A (zh) * 2020-11-10 2023-09-12 福霍恩治疗公司 化合物及其用途
PE20250261A1 (es) 2022-05-11 2025-01-29 Foghorn Therapeutics Inc Compuestos y usos de estos
CN116063183B (zh) * 2023-01-28 2023-06-27 山东国邦药业有限公司 一种环丙胺的合成方法

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612359A (en) 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides
TW536540B (en) 1997-01-30 2003-06-11 Bristol Myers Squibb Co Endothelin antagonists: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphe
BR9911621A (pt) 1998-07-06 2001-10-16 Bristol Myers Squibb Co Bifenil sulfonamidas como antagonista duplos de receptor de angiotensina endotelina
DE60042620D1 (de) * 1999-05-21 2009-09-03 Bristol Myers Squibb Co Pyrrolotriazine als Kinase Hemmer.
US6867300B2 (en) 2000-11-17 2005-03-15 Bristol-Myers Squibb Company Methods for the preparation of pyrrolotriazine compounds useful as kinase inhibitors
SK5402003A3 (en) * 2000-11-17 2004-06-08 Bristol Myers Squibb Co Methods of treating p38 kinase-associated conditions and pyrrolotriazine compounds useful as kinase inhibitors
TWI329112B (en) 2002-07-19 2010-08-21 Bristol Myers Squibb Co Novel inhibitors of kinases
US6951859B2 (en) 2002-08-02 2005-10-04 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
TW200420565A (en) * 2002-12-13 2004-10-16 Bristol Myers Squibb Co C-6 modified indazolylpyrrolotriazines
MXPA05008183A (es) 2003-02-05 2005-10-05 Bristol Myers Squibb Co Proceso para preparar pirrolotriazina como inhibidores de cinasa.
US7504521B2 (en) 2004-08-05 2009-03-17 Bristol-Myers Squibb Co. Methods for the preparation of pyrrolotriazine compounds
JP5046942B2 (ja) 2004-09-30 2012-10-10 テイボテク・フアーマシユーチカルズ Ｈｃｖ阻害性の二環式ピリミジン類
US7713973B2 (en) 2004-10-15 2010-05-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
KR20080107408A (ko) 2006-03-07 2008-12-10 브리스톨-마이어스 스큅 컴퍼니 키나제 억제제로서 유용한 피롤로트리아진 아닐린 전구약물화합물
WO2007107005A1 (en) 2006-03-22 2007-09-27 Methylgene, Inc. Inhibitors of protein tyrosine kinase activity
EA018322B1 (ru) 2006-07-07 2013-07-30 Бристол-Маерс Сквибб Компани ПРОИЗВОДНЫЕ ПИРРОЛО[1,2-f][1,2,4]ТРИАЗИНА
US7531539B2 (en) 2006-08-09 2009-05-12 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
WO2008057402A2 (en) 2006-11-02 2008-05-15 Cytovia, Inc. N-aryl-isoxazolopyrimidin-4-amines and related compounds as activators of caspases and inducers of apoptosis and the use thereof
CN101687874B (zh) 2007-04-18 2013-01-30 百时美施贵宝公司 吡咯并三嗪激酶抑制剂
US8058274B2 (en) * 2007-08-17 2011-11-15 Icagen, Inc. Heterocycles as potassium channel modulators
DE102007051762A1 (de) * 2007-10-30 2009-05-07 Bayer Healthcare Ag Substituierte Pyrrolotriazine und ihre Verwendung
US8212031B2 (en) 2008-03-06 2012-07-03 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
WO2010002472A1 (en) 2008-07-02 2010-01-07 Ambit Biosciences Corporation Jak kinase modulating compounds and methods of use thereof
JP5592890B2 (ja) * 2008-10-08 2014-09-17 ブリストル−マイヤーズ スクイブ カンパニー ピロロトリアジンキナーゼ阻害剤
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
WO2011018894A1 (en) * 2009-08-10 2011-02-17 Raqualia Pharma Inc. Pyrrolopyrimidine derivatives as potassium channel modulators
BR112012008330B1 (pt) * 2009-09-03 2022-03-22 Bristol-Myers Squibb Company Compostos quinazolinas, suas composições farmacêuticas e seus usos
US20120077814A1 (en) 2010-09-10 2012-03-29 Zhong Wang Sulfonamide, sulfamate, and sulfamothioate derivatives
JO3003B1 (ar) 2011-01-14 2016-09-05 Lilly Co Eli مركب أيميدازو [4، 5 -c ] كينولين-2- واحد واستخدامه كمثبط كيناز PI3/mtor
CN103373996A (zh) 2012-04-20 2013-10-30 山东亨利医药科技有限责任公司 作为crth2受体拮抗剂的二并环衍生物
HRP20180815T8 (hr) * 2012-06-11 2019-02-08 Bristol-Myers Squibb Company Prolijekovi fosforamidne kiseline 5-[5-fenil-4-(piridin-2-ilmetilamino)hinazolin-2-il]piridin-3-sulfonamida

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

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CN105008367A (zh) 2015-10-28
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